Arylpiperazine derivatives and their use as psychotropic agents

ABSTRACT

The invention relates to arylpiperazine derivatives of formula (I), wherein R 1 , R 2 , A, B, Ar and n have the given meanings.

[0001] The invention relates to arylpiperazine derivatives, theirpreparation and their use as psychopharmaceuticals.

[0002] The arylpiperazine derivatives according to the invention can berepresented by the general formula I

[0003] where

[0004] A is a fused heteroaromatic or heteroaliphatic ring comprisingone or two nitrogen atoms,

[0005] B is —CO— or —CHOH— or —C(Ar)(OH)—

[0006] R¹ and R² independently of one another are H, alkyl, C₁-C₆ orhalogen

[0007] Ar is phenyl or thiophene, which is unsubstituted ormonosubstituted or polysubstituted by halogen, NO₂ or CN and

[0008] n is 1, 2, 3 or 4,

[0009] and their salts and solvates.

[0010] Psychoses, which also include diseases of the schizophrenia type,have been attributed to a hyperactivity of the limbic dopamine system(Snyder et al., Science 184: 1243-1253, 1974). The antipsychotic effectof neuroleptics has been attributed to their D₂-antagonistic properties(with regard to the nomenclature of the receptors: Basic Neurochemistry,Editors: G. J. Siegel, B. W. Agranoff, R. W. Albers, P. B. Molinoff, 5thedition, Raven Press, Ltd, N.Y. USA, Chapters 12 and 13; otherwise thefollowing technical publications: Creese et al., Science 192: 481-483,1976; Farde et al., Psychopharmacology 99: 28-31, 1989; Feeman et al.,Nature 261: 717-719, 1976; Wiesel et al., Prog. Neuro-Psychopharmacol. &Biol. Psychiat. 14: 759-767, 1990). Consequently, the classical dopaminehypothesis of schizophrenia was formulated, according to whichneuroleptics have to bind to the D₂ receptor. On account of theirextrapyramidal side effects, the employment of classical D₂ antagonistsis severely restricted, especially in the case of chronicadministration. The extrapyramidal side effects include, for example,tremor, akinesia, dystonia and akathisia (Cavallaro & Smeraldi, CNSDrugs 4: 278-293, 1995). There are only a few antipsychotics which causesignificantly fewer or no extrapyramidal side effects at all and whichare described as “atypical neuroleptics” (Kervin, Brit. J. Psychiatry1964, 141-148, 1994). The prototype atypical neuroleptic clozapine hasextremely low extrapyramidal side effects, but causes other seriouscomplications such as agranulocytosis, which sometimes is fatal (Alviret al., New Engl. J. Med. 329: 162-167, 1993).

[0011] Because 5-HT_(1A) agonists intensify antipsychotic properties ofconventional dopamine D₂ antagonists in animals (Wadenberg & Ahlenios,J. Neural. Transm. 74: 195-198, 1988) and prevent the catalepsy inducedby dopamine D₂ antagonists (Costall et al., Neuropharmacology 14:859-868, 1975), 5-HT_(1A)-agonistic properties could be advantageous.The efficacy of buspirone, a pharmacon having 5-HT_(1A)-agonistic anddopamine D₂-antagonistic properties, has been demonstrated inschizophrenia patients (Goff et al., J. Clin, Psychopharmacol. 11:193-197, 1991). Apart from various dopamine autoreceptor agonists whichalso have a significant affinity for the 5-HT_(1A) receptor (e.g.U-86170F, Lahti et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 344:509-513, 1991), PD1431188 (Melzer et al., J. Pharmacol. Exp. Ther. 274:912-920, 1995) and roxindole (Bartoszyk et al., J. Pharmacol., Exp.Ther. 276: 41-48, 1996), only a few dopamine D₂ antagonists have beendeveloped which also have an affinity for the 5-HT_(1A) receptor, suchas mazapertine (Reiz et al., J. Mid. Chem. 37: 1060-1062, 1994), S16924(Millan et al., Br. J. Pharmacol. 114: 156 B, 1995) or ziprasidone(Seeger et al., J. Pharmacol. Exp. Ther. 275: 101-113, 1995). Thesealready known compounds have disadvantages with respect to affinity orspecificity. Thus mazapertine also shows an affinity for the α₁receptor. S16924 additionally has 5-HT_(2A/C)-antagonistic propertiesand ziprasidone moreover binds to the 5-HT_(1D/2A/2C) receptors.

[0012] It is the object of the invention to make available medicaments,in particular psychopharmaceuticals. It is a further object of theinvention to make available compounds which bind both to the dopamine D₂receptor and to the 5-HT_(1A) receptor.

[0013] This object is achieved by the compounds of the general formula Iand by their tolerable salts and solvates (see above).

[0014] It has been found that the compounds of the formula I and theirsalts have very valuable pharmacological properties together with goodtolerability. They especially act on the central nervous system. Theyhave, in particular, a high affinity for receptors of the 5-HT_(1A) typeand/or of the dopamine D₂ type.

[0015] Compounds of the formula I are particularly preferablysimultaneously agonists of the 5-HT_(1A) receptor and antagonists of theD₂ receptor. Binding to additional 5-HT_(1D/2A/2C) receptors is notobserved.

[0016] Binding properties of the compounds of the formula I can bedetermined by known 5-HT_(1A) (serotonin) binding test and dopaminebinding tests; (5-HT_(1A) (serotonin) binding test: Matzen et al., J.Med. Chem., 43, 1149-1157, (2000) in particular page 1156 with referenceto Eur. J. Pharmacol.: 140, 143-155 (1987); dopamine binding tests:Böttcher et al., J. Med. Chem.: 35, 4020-4026, (1992) with reference toJ. Neurochem.: 46, 1058-1067 (1986)).

[0017] The compound of the formula I differs from the abovementionedatypical neuroleptics.

[0018] The compounds according to the invention can be employed for thetreatment of diseases which are associated with the serotinin anddopamine neurotransmitter system and in which high-affinity serotininreceptors (5-HT_(1A) receptors) and/or dopamine D₂ receptors areinvolved. The most important indication for the administration of thecompound of the general formula I are psychoses of any type, inparticular also mental disorders of the schizophrenia type. Moreover,the compounds can also be employed for the reduction of cognitivefunctional disorders, i.e. for improvement of the learning ability andof the memory. The compounds of the general formula I are also suitablefor the control of the symptoms of Alzheimer's disease. The substancesof the general formula I according to the invention are moreoversuitable for the prophylaxis and control of cerebral infarcts (cerebralapoplexy), such as cerebral stroke and cerebral ischaemia. Thesubstances are also suitable for the treatment of disorders such aspathological anxiety states, overexcitation, hyperactivity and attentiondisorders in children and adolescents, deep-seated developmentaldisorders and disorders of social behaviour with mental retardation,depression, compulsive disorders in the narrower (OCD) and wider sense(OCSD), certain sexual function disorders, sleep disorders and eatingdisorders, and also such psychiatric symptoms in the context of seniledementia and dementia of the Alzheimer type, i.e. diseases of thecentral nervous system in the widest sense.

[0019] The compounds of the general formula I and their tolerable saltsand solvates can thus be employed as active ingredients of medicamentssuch as anxiolytics, antidepressants, neuroleptics and/orantihypertensives.

[0020] Ar is preferably a phenyl group which is optionally mono-, di-,tri-, tetra- or pentasubstituted by one or more groups Hal, —NO₂ or —CN.Ar can furthermore carry the meaning of a thiophenyl group which isoptionally mono- or disubstituted by one or more of the groups Hal, NO₂or —CN. Ar is in particular fluorophenyl, difluorophenyl, cyanophenyl ortolyl. Very particularly preferably, Ar has the meaning 3-fluorophenyl,2,4-difluorophenyl, 3-cyanophenyl or 4-fluorophenyl, in particular4-fluorophenyl.

[0021] B preferably carries the meaning —CO— or —C(Ar)(OH)—, inparticular —C(4-fluorophenyl)(OH)—.

[0022] R¹ and R² are, independently of one another, preferably H orC₁-C₆-alkyl, where 1 to 7 hydrogen atoms are optionally replaced byfluorine. R¹ and/or R² can be branched or unbranched and is preferablymethyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbuytyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl. Particularly preferably, R¹ and/or R² is methyl,ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.

[0023] Compounds of the formula I are also particularly preferred inwhich R¹ and R² are simultaneously H, and compounds of the formula I inwhich R¹ has the meaning alkyl and R² has the meaning H.

[0024] The group

[0025] preferably has one of the following meanings:

[0026] Very particularly preferred meanings are

[0027] Hal is F, Cl, Br or I , where F and Cl, in particular F, arepreferred.

[0028] n is preferably 1, 2 or 3, where n equals 3 is particularlypreferred.

[0029] The substituents R¹, R², A, B and Ar can independently of oneanother assume one of the abovementioned meanings. The compounds of thegeneral formula I are thus all the more strongly preferred, the more oftheir substituents have preferred meanings and the greater thesemeanings are preferred.

[0030] Compounds selected from the following group of the compounds Iato 1h are particularly preferred:

[0031] and their salts and solvates.

[0032] If the compounds of the general formula I are optically active,the formula I includes both any isolated optical antipodes and thecorresponding optionally racemic mixtures in any conceivablecomposition.

[0033] A compound of the general formula I can be converted into thecorresponding salt (that is acid addition salt) using an acid. Acidswhich afford the tolerable (that is biocompatible and adequatelybioavailable) salts are suitable for this reaction. It is thus possibleto use inorganic acids such as sulfuric acid or hydrohalic acids such ashydrochloric acid, bromic acid or phosphoric acids such asorthophosphoric acid, nitric acid, sulfamic acid, aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylicacids, sulfonic acids or sulfuric acid derivatives such as formic acid,acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonicacid, succinic acid, pimelic acid, fumaric acid, maleic acid, lacticacid, tartaric acid, malic acid, benzoic acid, salicylic acid,2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methanesulfonic acid orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, paratoluenesulfonic acid,naphthalenemonosulfonic acid and naphthalenedisulfonic acid sulfuricacid lauryl ester in order to obtain the corresponding acid additionsalt.

[0034] If desired, the corresponding free bases of the general formula Ican be liberated by the treatment of their salts with strong bases suchas sodium hydroxide, potassium hydroxide or sodium or potassiumcarbonate, provided that no other acidic groups are present in themolecule. In the last-mentioned cases, in which the compounds of thegeneral formula I carry free acidic groups, salt formation can also bebrought about by treatment with strong bases. Suitable bases are alkalimetal hydroxides, alkaline earth metal hydroxides, or organic bases inthe form of primary, secondary or tertiary amines.

[0035] Solvates of the compounds of the general formula I are understoodas meaning adducts of chemically “inert” solvent molecules to thecompounds of the formula I which are formed on account of their mutualattractive force. Solvates are, for example, mono- and dihydrates oraddition compounds with alcohols such as methanol or ethanol.

[0036] It is known that pharmaceuticals can be converted syntheticallyinto derivatives (for example into alkyl or acyl derivatives, into sugaror oligopeptide derivatives and others) which are converted back intothe active compounds of the general formula I in the body metabolicallyby extracellular or intracellular enzymes. The invention also relates tosuch “prodrug derivatives” of the compounds of the general formula I.

[0037] A further subject of the invention is the use of a compound ofthe general formula I or of one of its tolerable salts or solvates forthe production of a medicament which is suitable for the treatment ofhuman or animal disorders, in particular of disorders of the centralnervous system such as pathological stress states, depression and/orpsychoses, for the reduction of side effects during the treatment ofhigh blood pressure (e.g. with α-methyldopa), for the, treatment ofendocrinological and/or gynaecological disorders, e.g. for the treatmentof acromegaly, hypogonadism, secondary amenorrhoea, the post-menstrualsyndrome and undesired lactation in puberty and for the prophylaxis andtherapy of cerebral disorders (e.g. of migraine), in particular ingeriatrics, in a similar manner to specific ergot alkaloids and for thecontrol and prophylaxis of cerebral infarct (cerebral apoplexy) such ascerebral stroke and cerebral ischaemia. Moreover, the pharmaceuticalpreparations and medicaments which contain a compound of the generalformula I are suitable for improvement of the cognitive functionalability and for the treatment of Alzheimer's disease symptoms. Inparticular, such medicaments are suitable for the treatment of mentaldisorders of the schizophrenia type and for the control of psychoticanxiety states. The term treatment in the context of the inventionincludes prophylaxis and therapy of human or animal diseases.

[0038] The substances of the general formula I are normally administeredanalogously to known, commercially obtainable pharmaceuticalpreparations (e.g. of bromocriptine and dihydroergocornine), preferablyin doses of between 0.2 and 500 mg, in particular of between 0.2 and 15mg per dose unit. The daily dose unit is between 0.001 and 10 mg per kgof body weight. Low doses (of between 0.2 and 1 mg per dose unit, 0.001to 0.005 mg per kg of body weight) are particularly suitable forpharmaceutical preparations for the treatment of migraine. A dose ofbetween 10 and 50 mg per dose unit is preferred for other indications.However, the dose to be administered depends on a large number offactors, e.g. on the efficacy of the corresponding component, the age,the body weight and the general condition of the patient.

[0039] The invention also relates to the compounds of the formula Iaccording to Claim 1 and their physiologically acceptable salts orsolvates as pharmaceutical active compounds.

[0040] The invention furthermore relates to compounds of the formula Iaccording to Claim 1 and their physiologically acceptable salts orsolvates as D₂ receptor antagonists and 5HT_(1A) agonists.

[0041] The invention also relates to the compounds of the formula Iaccording to Claim 1 and their physiologically acceptable salts orsolvates for use in the control of diseases.

[0042] A further subject of the invention is a process for theproduction of a pharmaceutical preparation, which comprises theconversion of a compound of the general formula I or of one of itstolerable salts or solvates to a suitable dose form together with asuitable vehicle. The compounds of the general formula I can be broughtinto a suitable dose form together with at least one vehicle orexcipient, if appropriate in combination with a further activeingredient.

[0043] Suitable vehicles are organic or inorganic substances which aresuitable for enteral (e.g. oral) or parenteral or topical administrationand which do not react with the substances of the general formula Iaccording to the invention. Examples of such vehicles are water,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin,carbohydrates such as lactose and starch, magnesium stearate, talc andraw petroleum jelly. Tablets, coated tablets, capsules, syrups, juices,drops or suppositories are in particular employed for enteraladministration. Solutions, preferably oily or aqueous solutions, such assuspensions, emulsions or alternatively implants are used for parenteraladministration. Ointments, creams or powders are employed in the case ofexternal application. The compounds of the general formula I can also belyophilized and the resulting lyophilizates processed to give injectablepreparations.

[0044] The invention further relates to medicaments which contain atleast one compound of the general formula I or one of its tolerablesalts or solvates and, if appropriate, further ingredients such asvehicles, excipients etc. These preparations can be employed asmedicaments for the treatment of human or animal diseases.

[0045] The aforementioned medicaments can be sterilized and processedtogether with excipients such as lubricants, preservatives, stabilizersand/or wetting agents, emulsifiers, osmotically active substances,buffers, colorants or flavor enhancers to give other pharmaceuticalpreparations.

[0046] A further subject of the invention is a process for thepreparation of compounds of the formula I, and their salts and solvates,characterized in that

[0047] (a) a compound of the formula II

[0048]  in which R¹, R² and A have the meanings indicated above, isreacted with a compound of the formula III

[0049]  in which Ar, B and n have the meanings indicated above and L isa leaving group, in particular Cl, tosylate or Br, and if B has themeaning —CO— the group B is optionally hydrogenated, alkylated orarylated and, if appropriate, a basic or acidic compound of the formulaI is converted into one of its salts or solvates by treating with anacid or base. Grignard or organolithium reagents are preferably used forthe alkylation and arylation and a complex hydride is preferably usedfor the hydrogenation.

[0050] The compounds of the formula I and also the starting substancesfor their preparation are otherwise prepared by methods known per se,such as are described in the literature (e.g. in the standard works suchas Houben-Weyl, Methoden der organischen Chemie [Methods of organicchemistry], Georg-Thieme-Verlag, Stuttgart), namely under reactionconditions which are known and suitable for the reactions mentioned. Usecan also be made in this case of variants which are known per se, butnot mentioned here in greater detail.

[0051] If desired, the starting substances can also be formed in situsuch that they are not isolated from the reaction mixture, butimmediately reacted further to give the compounds of the formula I.

[0052] The arylpiperazine derivatives of the formula I are preferablyprepared according to the following scheme:

[0053] in which A, R¹ and R² have the meanings indicated above.

[0054] The invention is described by the following examples.

[0055] The molecular weight (M+H⁺) is determined with the aid ofelectron spray ionization mass spectroscopy. The mass-spectroscopic dataderive from HPLC/MS runs (HPLC coupled with an electrospray ionizationmass spectrometer). The numerical values are, as customary in thisprocedure, not the molecular weights of the unmodified compounds, butthe molecular weights of the protonated compounds (below: [M+H⁺]). Themethod is described in the following references: M. Yamashita, J. B.Fenn, J. Phys. Chem. 88, 1984, 4451-4459; C. K. Meng et al., Zeitschriftfür Physik D 10, 1988, 361-368; J. B. Fenn et al., Science 246, 1989,64-71.

EXAMPLE 14-[4-(Quinolin-8-yl)piperazin-1-yl]-1-(4-fluorophenyl)butan-1-onetrichloride dihydrate

[0056]

[0057] 6 g of 1-(Quinolin-8-yl)piperazine 1 and 2.8 g of4-chloro-1-(4-fluorophenyl)butan-1-one 2 were heated together at 120°(bath temperature) for 1 hour. The mixture was cooled, treated withwater and extracted with ethyl acetate. After drying over potassiumcarbonate, the ethyl acetate was distilled off and the residue waschromatographed on silica gel, whereby 3 was obtained.

[0058] For the formation of the acid addition salt, 700 mg of 3 weredissolved in 20 ml of ethyl acetate and acidified with ethanolic HCl.The crystallized hydrochloride was filtered off with suction and washedwith ethyl acetate (m.p. 119-120°, [M+H]⁺: 378).

EXAMPLE 24-[4-(Quinolin-8-yl)piperazin-1-yl]-1-(4-fluorophenyl)butan-1-olfumarate

[0059]

[0060] 1.3 g of4-[4-(Quinolin-8-yl)piperazin-1-yl]-1-(4-fluorophenyl)butan-1-one 3 weredissolved in 25 ml of methanol and 264 mg of sodium borohydride wereadded in portions with stirring and cooling. The mixture wasadditionally stirred at R.T. for a further two hours, then the methanolwas distilled off in vacuo. The residue was treated with water, renderedalkaline with 32% NaOH and extracted with dichloromethane. After dryingover potassium carbonate, the dichloromethane was distilled off and theresidue was chromatographed on silica gel, whereby 4 was obtained. Theresidue was dissolved with warming in 20 ml of ethanol with 337 mg offumaric acid and the solution obtained was evaporated in vacuo. Theresidue was treated with ethyl acetate, and the crystallized fumaratewas filtered off with suction and washed with ethyl acetate (m.p.145-146°, [M+H]⁺: 380).

EXAMPLE 31,1-bis-(4-Fluorophenyl)-4-[4-(2-methylquinolin-8-yl)piperazin-1-yl]-1-butanolfumarate

[0061]

[0062] 2.2 g of1-(4-Fluorophenyl)-4-[4-(quinolin-8-yl)piperazin-1-yl]butan-1-one 3 in20 ml of abs. tetrahydrofuran was added dropwise at R.T. to a Grignardsolution of 423 mg of magnesium turnings and 3.05 g of1-bromo-4-fluorobenzene in 30 ml of abs. tetrahydrofuran. The mixturewas stirred overnight at R.T., then 25 ml of 10% ammonium chloridesolution were added dropwise with cooling and the mixture was extractedwith ethyl acetate. After drying over potassium carbonate, the ethylacetate was distilled off and the residue was chromatographed on silicagel, whereby 5 was obtained. The residue was dissolved with warming in30 ml of ethanol with 290 mg of fumaric acid. The solution was cooled,and the crystallized fumarate was filtered off with suction and washedwith ethanol and ethyl acetate (m.p. 219-220°, M⁺: 473).

EXAMPLE 41-(4-Fluorophenyl)-4-[4-(2-methylquinolin-8-yl)piperazin-1-yl]butan-1-onehemifumarate

[0063]

[0064] 3.53 g of 4-chloro-1-(4-fluorophenyl)butan-1-one 2 were added to4 g of 1-(2-methylquinolin-8-yl)piperazine 6, 2.43 g of potassiumcarbonate and 20 mg of potassium iodide in 60 ml of acetonitrile and themixture was stirred at 80° for 87 hours in a heating block. Theacetonitrile was then distilled off in vacuo, and the residue wastreated with water and extracted with dichloromethane. After drying overpotassium carbonate, the dichloromethane was distilled off and theresidue was chromatographed on silica gel, whereby 7 was obtained.

[0065] For the formation of the acid addition salts, 1.2 g of 7 weredissolved with warming in 15 ml of ethanol with 348 mg of fumaric acid.The fumarate which crystallized on cooling was filtered off with suctionand washed with ethanol (m.p. 195-196°, [M+H]⁺: 392).

EXAMPLE 54-[4-(2-Methylquinolin-8-yl)piperazin-1-yl]-1-(4-fluorophenyl)butan-1-olsesquifumarate

[0066]

[0067] Analogously to Example 2, using 1.3 g (0.0033 mol) of4-[4-(2-methylquinolin-8-yl)piperazin-1-yl]-1-(4-fluorophenyl)butan-1-one 7, 249 mg (0.0066 mol) of sodiumborohydride and 25 ml of methanol, the compound 8 was obtained.

[0068] For the formation of the acid addition salts, 830 mg of 8 weredissolved with warming in 10 ml of ethanol with 244 mg of fumaric acidand the solution was evaporated in vacuo. The residue was treated withethyl acetate and the crystal obtained were filtered off with suctionand washed with ethyl acetate (m.p. 164-165°, [M+H]⁺: 394).

EXAMPLE 6 1,1-bis(4-Fluorophenyl)-4-[4-(2-methylquinolin-8-yl)-1-butanolhemifumarate ethanoate

[0069]

[0070] Analogously to Example 3, using 539 mg of magnesium turnings, 3.9g (0.022 mol) of 1-bromo-4-fluorobenzene, 2.9 g (0.007 mol) of1-(4-fluorophenyl)-4-[4-(2-methylquinolin-8- yl)piperazin-1-yl]butan-1-one 7 and 50 ml of abs. tetrahydrofuran

[0071] the compound 9 was obtained.

[0072] For the formation of the acid addition salt, 2.3 g 9 weredissolved with warming in 20 ml of ethanol with 545 mg of fumaric acid.The fumarate which crystallized after cooling was filtered off withsuction and washed with ethyl acetate (m.p. 129-130°, [M+H]⁺: 488).

EXAMPLE 7 4-[4-(Indol-4-yl)piperazin-1-yl]-1-(4-fluorophenyl)butan-1-onedihydrochloride

[0073]

[0074] Analogously to Example 4, using 4 g (0.02 mol) of1-(indol-4-yl)piperazine 10, 4 g (0.02 mol) of4-chloro-1-(4-fluorophenyl)butan-1-one 2, 2.8 g (0.02 mol) of potassiumcarbonate, 40 mg of potassium iodide and 75 ml of acetonitrile, thecompound 11 was obtained.

[0075] For the formation of the acid addition salt, 800 mg of base weredissolved in 10 ml of ethanol with warming and acidified withethanol/HCl. The hydrochloride which crystallized after cooling wasfiltered off with suction and washed with ethanol and ether (m.p.233-234°, [M+H]⁺: 366).

EXAMPLE 8 4-[4-(Indol-4-yl)piperazin-1-yl]-1-(4-fluorophenyl)-1-butanoldihydrochloride

[0076]

[0077] Analogously to Example 2, using 1.29 (0.0033 mol) of4-[4-(indol-4-yl)piperazin-1-yl]-1-(4-fluoro- phenyl)butan-1-one 11, 250mg (0.0066 mol) of sodium borohydride and a mixture of 30 ml of methanoland 20 ml of dichloromethane, the compound 12 was obtained.

[0078] For the formation of the acid addition salt, 1.1 g of 12 weredissolved in ethanol with warming and acidified with ethanolic HCl. Thehydrochloride which crystallized after cooling was filtered off withsuction and washed with ethanol and ether (m.p. 227-22820 , [M+H]⁺:368).

[0079] The following compounds and their acid addition salts areprepared analogously using the appropriate precursors.

EXAMPLES 9-76

[0080]

R¹ R² B Ar  (9) H H —CO— p-C₆H₄CN (10) H H —CO— o-C₆H₄F (11) H H —CO—m-C₆H₄F (12) H H —CO— p-C₆H₄Cl (13) H H —CO— m-C₆H₄Cl (14) H H —CO— C₆H₅(15) H H —CO— 2-C₄H₃S (16) H H —CH(OH)— p-C₅H₄CN (17) H H —CH(OH)—o-C₆H₄F (18) H H —CH(OH)— m-C₆H₄F (19) H H —CH(OH)— p-C₆H₄Cl (20) H H—CH(OH)— m-C₆H₄Cl (21) H H —CH(OH)— C₆H₅ (22) H H —CH(OH)— 2-C₄H₃S (23)H H —C(p-C₆H₄F)(OH)— p-C₆H₄CN (24) H H —C(p-C₆H₄F)(OH)— o-C₆H₄F (25) H H—C(p-C₆H₄F)(OH)— m-C₆H₄F (26) H H —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (27) H H—C(p-C₆H₄F)(OH)— m-C₆H₄Cl (28) H H —C(p-C₆H₄F)(OH)— C₆H₅ (29) H H—C(p-C₆H₄F)(OH)— 2-C₄H₃S (30) H H —C(C₆H₅)(OH)— p-C₆H₄F (31) H H—C(C₆H₅)(OH)— o-C₆H₄F (32) H H —C(C₆H₅)(OH)— m-C₆H₄F (33) H H—C(C₆H₅)(OH)— p-C₆H₄Cl (34) H H —C(C₆H₅)(OH)— m-C₆H₄Cl (35) H H—C(C₆H₅)(OH)— C₆H₅ (36) H H —C(C₆H₅)(OH)— 2-C₄H₃S (37) H CH₃ —CO—p-C₆H₄F (38) H CH₃ —CO— o-C₆H₄F (39) H CH₃ —CO— m-C₆H₄F (40) H CH₃ —CO—p-C₆H₄F (41) H CH₃ —CO— m-C₆H₄F (42) H CH₃ —CO— C₆H₅ (43) H CH₃ —CO—2-C₄H₃S (44) H CH₃ —CH(OH)— p-C₆H₄F (45) H CH₃ —CH(OH)— o-C₆H₄F (46) HCH₃ —CH(OH)— m-C₆H₄F (47) H CH₃ —CH(OH)— p-C₆H₄Cl (48) H CH₃ —CH(OH)—m-C₆H₄Cl (49) H CH₃ —CH(OH)— C₆H₅ (50) H CH₃ —CH(OH)— 2-C₄H₃S (51) H CH₃—C(p-C₆H₄F)(OH)— p-C₆H₄F (52) H CH₃ —C(p-C₆H₄F)(OH)— o-C₆H₄F (53) H CH₃—C(p-C₆H₄F)(OH)— m-C₆H₄F (54) H CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (55) H CH₃—C(p-C₆H₄F)(OH)— m-C₆H₄Cl (56) H CH₃ —C(p-C₆H₄F)(OH)— C₆H₅ (57) H CH₃—C(p-C₆H₄F)(OH)— 2-C₄H₃S (58) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (59) H CH₃—C(C₆H₅)(OH)— o-C₆H₄F (60) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄F (61) H CH₃—C(C₆H₅)(OH)— p-C₆H₄Cl (62) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄Cl (63) H CH₃—C(C₆H₅)(OH)— C₆H₅ (64) H CH₃ —C(C₆H₅)(OH)— 2-C₄H₃S (65) CH₃ H —CO—p-C₆H₄CN (66) CH₃ H —C(C₆H₅)(OH)— p-C₆H₄F (67) CH₃ H —C(C₆H₅)(OH)—p-C₆H₄CN (68) CH₃ H —CH(OH)— p-C₆H₄CN (69) H F —CO— p-C₆H₄F (70) H F—C(C₆H₅)(OH)— p-C₆H₄F (71) H F —C(p-C₆H₄F)(OH)— p-C₆H₄F (72) H Cl—CH(OH)— p-C₆H₄F (73) F CH₃ —CO— p-C₆H₄F (74) F CH₃ —C(C₆H₅)(OH)—p-C₆H₄F (75) F CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F (76) Cl CH₃ —CH(OH)— p-C₆H₄F

EXAMPLES 77-144

[0081]

R¹ R² B Ar  (77) H Cl —CO— p-C₆H₄F  (78) H Cl —CO— o-C₆H₄F  (79) H Cl—CO— m-C₆H₄F  (80) H Cl —CO— p-C₆H₄Cl  (81) H Cl —CO— m-C₆H₄Cl  (82) HCl —CO— C₆H₅  (83) H Cl —CO— 2-C₄H₃S  (84) H Cl —CH(OH)— p-C₆H₄F  (85) HCl —CH(OH)— o-C₆H₄F  (86) H Cl —CH(OH)— m-C₆H₄F  (87) H Cl —CH(OH)—p-C₆H₄Cl  (88) H Cl —CH(OH)— m-C₆H₄Cl  (89) H Cl —CH(OH)— C₆H₅  (90) HCl —CH(OH)— 2-C₄H₃S  (91) H Cl —C(p-C₆H₄F)(OH)— p-C₆H₄F  (92) H Cl—C(p-C₆H₄F)(OH)— o-C₆H₄F  (93) H Cl —C(p-C₆H₄F)(OH)— m-C₆H₄F  (94) H Cl—C(p-C₆H₄F)(OH)— p-C₆H₄Cl  (95) H Cl —C(p-C₆H₄F)(OH)— m-C₆H₄Cl  (96) HCl —C(p-C₆H₄F)(OH)— C₆H₅  (97) H Cl —C(p-C₆H₄F)(OH)— 2-C₄H₃S  (98) H Cl—C(C₆H₅)(OH)— p-C₆H₄F  (99) H F —C(C₆H₅)(OH)— o-C₆H₄F (100) H F—C(C₆H₅)(OH)— m-C₆H₄F (101) H F —C(C₆H₅)(OH)— p-C₆H₄Cl (102) H F—C(C₆H₅)(OH)— m-C₆H₄Cl (103) H F —C(C₆H₅)(OH)— C₆H₅ (104) H F—C(C₆H₅)(OH)— 2-C₄H₃S (105) H CH₃ —CO— p-C₆H₄F (106) H CH₃ —CO— o-C₆H₄F(107) H CH₃ —CO— m-C₆H₄F (108) H CH₃ —CO— p-C₆H₄Cl (109) H CH₃ —CO—m-C₆H₄Cl (110) H CH₃ —CO— C₆H₅ (111) H CH₃ —CO— 2-C₄H₃S (112) H CH₃—CH(OH)— p-C₆H₄F (113) H CH₃ —CH(OH)— o-C₆H₄F (114) H CH₃ —CH(OH)—m-C₆H₄F (115) H CH₃ —CH(OH)— p-C₆H₄Cl (116) H CH₃ —CH(OH)— m-C₆H₄Cl(117) H CH₃ —CH(OH)— C₆H₅ (118) H CH₃ —CH(OH)— 2-C₄H₃S (119) H CH₃—C(p-C₆H₄F)(OH)— p-C₆H₄F (120) H CH₃ —C(p-C₆H₄F)(OH)— o-C₆H₄F (121) HCH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄F (122) H CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (123)H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄Cl (124) H CH₃ —C(p-C₆H₄F)(OH)— C₆H₅ (125)H CH₃ —C(p-C₆H₄F)(OH)— 2-C₄H₃S (126) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (127) HCH₃ —C(C₆H₅)(OH)— o-C₆H₄F (128) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄F (129) H CH₃—C(C₆H₅)(OH)— p-C₆H₄Cl (130) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄Cl (131) H CH₃—C(C₆H₅)(OH)— C₆H₅ (132) H CH₃ —C(C₆H₅)(OH)— 2-C₄H₃S (133) CH₃ Cl —CO—p-C₆H₄F (134) CH₃ Cl —C(C₆H₅)(OH)— p-C₆H₄F (135) CH₃ Cl —C(C₆H₄F)(OH)—p-C₆H₄F (136) CH₃ Cl —CH(OH)— p-C₆H₄F (137) H F —CO— p-C₆H₄F (138) H F—C(C₆H₅)(OH)— p-C₆H₄F (139) H F —C(p-C₆H₄F)(OH)— p-C₆H₄F (140) H Cl—CH(OH)— p-C₆H₄F (141) F CH₃ —OH— p-C₆H₄F (142) F CH₃ —C(C₆H₅)(OH)—p-C₆H₄F (143) F CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F (144) Cl CH₃ —CH(OH)—p-C₆H₄F

EXAMPLES 145-212

[0082]

R¹ R² B Ar (145) CH₃ H —CO— p-C₆H₄F (146) CH₃ H —CO— o-C₆H₄F (147) CH₃ H—CO— m-C₆H₄F (148) CH₃ H —CO— p-C₆H₄Cl (149) CH₃ H —CO— m-C₆H₄Cl (150)CH₃ H —CO— C₆H₅ (151) CH₃ H —CO— 2-C₄H₃S (152) CH₃ H —CH(OH)— p-C₆H₄F(153) CH₃ H —CH(OH)— o-C₆H₄F (154) CH₃ H —CH(OH)— m-C₆H₄F (155) CH₃ H—CH(OH)— p-C₆H₄Cl (156) CH₃ H —CH(OH)— m-C₆H₄Cl (157) CH₃ H —CH(OH)—C₆H₅ (158) CH₃ H —CH(OH)— 2-C₄H₃S (159) CH₃ H —C(p-C₅H₄F)(OH)— p-C₆H₄F(160) CH₃ H —C(p-C₅H₄F)(OH)— o-C₆H₄F (161) CH₃ H —C(p-C₅H₄F)(OH)—m-C₆H₄F (162) CH₃ H —C(p-C₅H₄F)(OH)— p-C₆H₄Cl (163) CH₃ H—C(p-C₅H₄F)(OH)— m-C₆H₄Cl (164) CH₃ H —C(p-C₅H₄F)(OH)— C₆H₅ (165) CH₃ H—C(p-C₅H₄F)(OH)— 2-C₄H₃S (166) CH₃ H —C(C₆H₅)(OH)— p-C₆H₄F (167) CH₃ H—C(C₆H₅)(OH)— o-C₆H₄F (168) CH₃ H —C(C₆H₅)(OH)— m-C₆H₄F (169) CH₃ H—C(C₆H₅)(OH)— p-C₆H₄Cl (170) CH₃ H —C(C₆H₅)(OH)— m-C₆H₄Cl (171) CH₃ H—C(C₆H₅)(OH)— C₆H₅ (172) CH₃ H —C(C₆H₅)(OH)— 2-C₄H₃S (173) CH₃ CH₃ —CO—p-C₆H₄F (174) CH₃ CH₃ —CO— o-C₆H₄F (175) CH₃ CH₃ —CO— m-C₆H₄F (176) CH₃CH₃ —CO— p-C₆H₄Cl (177) CH₃ CH₃ —CO— m-C₆H₄Cl (178) CH₃ CH₃ —CO— C₆H₅(179) CH₃ CH₃ —CO— 2-C₄H₃S (180) CH₃ CH₃ —CH(OH)— p-C₆H₄F (181) CH₃ CH₃—CH(OH)— o-C₆H₄F (182) CH₃ CH₃ —CH(OH)— m-C₆H₄F (183) CH₃ CH₃ —CH(OH)—p-C₆H₄Cl (184) CH₃ CH₃ —CH(OH)— m-C₆H₄Cl (185) CH₃ CH₃ —CH(OH)— C₆H₅(186) CH₃ CH₃ —CH(OH)— 2-C₄H₃S (187) CH₃ CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F(188) CH₃ CH₃ —C(p-C₆H₄F)(OH)— o-C₆H₄F (189) CH₃ CH₃ —C(p-C₆H₄F)(OH)—m-C₆H₄F (190) CH₃ CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (191) CH₃ CH₃—C(p-C₆H₄F)(OH)— m-C₆H₄Cl (192) CH₃ CH₃ —C(p-C₆H₄F)(OH)— C₆H₅ (193) CH₃CH₃ —C(p-C₆H₄F)(OH)— 2-C₄H₃S (194) CH₃ CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (195)CH₃ CH₃ —C(C₆H₅)(OH)— o-C₆H₄F (196) CH₃ CH₃ —C(C₆H₅)(OH)— m-C₆H₄F (197)CH₃ CH₃ —C(C₆H₅)(OH)— p-C₆H₄Cl (198) CH₃ CH₃ —C(C₆H₅)(OH)— m-C₆H₄Cl(199) CH₃ CH₃ —C(C₆H₅)(OH)— C₆H₅ (200) CH₃ CH₃ —C(C₆H₅)(OH)— 2-C₄H₃S(201) CH₃ H —CO— p-C₆H₄F (202) CH₃ H —C(C₆H₅)(OH)— p-C₆H₄F (203) CH₃ H—C(C₆H₅)(OH)— p-C₆H₄F (204) CH₃ H —CH(OH)— p-C₆H₄F (205) Cl F —CO—p-C₆H₄F (206) Cl F —C(C₆H₅)(OH)— p-C₆H₄F (207) F F —C(p-C₆H₄F)(OH)—p-C₆H₄F (208) F Cl —CH(OH)— p-C₆H₄F (209) F CH₃ —CO— p-C₆H₄F (210) F CH₃—C(C₆H₅)(OH)— p-C₆H₄F (211) F CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F (212) Cl CH₃—CH(OH)— p-C₆H₄F

EXAMPLES 213-280

[0083]

R¹ R² B Ar (213) H H —CO— p-C₆H₄F (214) H H —CO— o-C₆H₄F (215) H H —CO—m-C₆H₄F (216) H H —CO— p-C₆H₄Cl (217) H H —CO— m-C₆H₄Cl (218) H H —CO—C₆H₅ (219) H H —CO— 2-C₄H₃S (220) H H —CH(OH)— p-C₆H₄F (221) H H—CH(OH)— o-C₆H₄F (222) H H —CH(OH)— m-C₆H₄F (223) H H —CH(OH)— p-C₆H₄Cl(224) H H —CH(OH)— m-C₆H₄Cl (225) H H —CH(OH)— C₆H₅ (226) H H —CH(OH)—2-C₄H₃S (227) H H —C(p-C₆H₄F)(OH)— p-C₆H₄F (228) H H —C(p-C₆H₄F)(OH)—o-C₆H₄F (229) H H —C(p-C₆H₄F)(OH)— m-C₆H₄F (230) H H —C(p-C₆H₄F)(OH)—p-C₆H₄Cl (231) H H —C(p-C₆H₄F)(OH)— m-C₆H₄Cl (232) H H —C(p-C₆H₄F)(OH)—C₆H₅ (233) H H —C(p-C₆H₄F)(OH)— 2-C₄H₃S (234) H H —C(C₆H₅)(OH)— p-C₆H₄F(235) H H —C(C₆H₅)(OH)— o-C₆H₄F (236) H H —C(C₆H₅)(OH)— m-C₆H₄F (237) HH —C(C₆H₅)(OH)— p-C₆H₄Cl (238) H H —C(C₆H₅)(OH)— m-C₆H₄Cl (239) H H—C(C₆H₅)(OH)— C₆H₅ (240) H H —C(C₆H₅)(OH)— 2-C₄H₃S (241) H CH₃ —CO—p-C₆H₄F (242) H CH₃ —CO— o-C₆H₄F (243) H CH₃ —CO— m-C₆H₄F (244) H CH₃—CO— p-C₆H₄Cl (245) H CH₃ —CO— m-C₆H₄Cl (246) H CH₃ —CO— C₆H₅ (247) HCH₃ —CO— 2-C₄H₃S (248) H CH₃ —CH(OH)— p-C₆H₄F (249) H CH₃ —CH(OH)—o-C₆H₄F (250) H CH₃ —CH(OH)— m-C₆H₄F (251) H CH₃ —CH(OH)— p-C₆H₄Cl (252)H CH₃ —CH(OH)— m-C₆H₄Cl (253) H CH₃ —CH(OH)— C₆H₅ (254) H CH₃ —CH(OH)—2-C₄H₃S (255) H CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F (256) H CH₃—C(p-C₆H₄F)(OH)— o-C₆H₄F (257) H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄F (258) HCH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (259) H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄Cl(260) H CH₃ —C(p-C₆H₄F)(OH)— C₆H₅ (261) H CH₃ —C(p-C₆H₄F)(OH)— 2-C₄H₃S(262) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (263) H CH₃ —C(C₆H₅)(OH)— o-C₆H₄F(264) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄F (265) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄Cl(266) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄Cl (267) H CH₃ —C(C₆H₅)(OH)— C₆H₅ (268)H CH₃ —C(C₆H₅)(OH)— 2-C₄H₃S (269) CH₃ H —CO— p-C₆H₄F (270) CH₃ H—C(C₆H₅)(OH)— p-C₆H₄F (271) CH₃ H —C(C₆H₅)(OH)— p-C₆H₄CN (272) CH₃ H—CH(OH)— p-C₆H₄F (273) H F —CO— p-C₆H₄F (274) H F —C(C₆H₅)(OH)— p-C₆H₄F(275) H F —C(p-C₆H₄F)(OH)— p-C₆H₄F (276) H Cl —CH(OH)— p-C₆H₄F (277) FCH₃ —CO— p-C₆H₄F (278) F CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (279) F CH₃—C(p-C₆H₄F)(OH)— p-C₆H₄F (280) Cl CH₃ —CH(OH)— p-C₆H₄F

EXAMPLES 281-348

[0084]

R¹ R² B Ar (281) H H —CO— p-C₆H₄CN (282) H H —CO— o-C₆H₄F (283) H H —CO—m-C₆H₄F (284) H H —CO— p-C₆H₄Cl (255) H H —CO— m-C₆H₄Cl (286) H H —CO—C₆H₅ (287) H H —CO— 2-C₄H₃S (288) H H —CH(OH)— p-C₆H₄CN (289) H H—CH(OH)— o-C₆H₄F (290) H H —CH(OH)— m-C₆H₄F (291) H H —CH(OH)— p-C₆H₄Cl(292) H H —CH(OH)— m-C₆H₄Cl (293) H H —CH(OH)— C₆H₅ (294) H H —CH(OH)—2-C₄H₃S (295) H H —C(p-C₆H₄F)(OH)— p-C₆H₄F (296) H H —C(p-C₆H₄F)(OH)—o-C₆H₄F (297) H H —C(p-C₆H₄F)(OH)— m-C₆H₄F (298) H H —C(p-C₆H₄F)(OH)—p-C₆H₄Cl (299) H H —C(p-C₆H₄F)(OH)— m-C₆H₄Cl (300) H H —C(p-C₆H₄F)(OH)—C₆H₅ (301) H H —C(p-C₆H₄F)(OH)— 2-C₄H₃S (302) H H —C(C₆H₅)(OH)— p-C₆H₄CN(303) H H —C(C₆H₅)(OH)— o-C₆H₄F (304) H H —C(C₆H₅)(OH)— m-C₆H₄F (305) HH —C(C₆H₅)(OH)— p-C₆H₄Cl (306) H H —C(C₆H₅)(OH)— m-C₆H₄Cl (307) H H—C(C₆H₅)(OH)— C₆H₅ (308) H H —C(C₆H₅)(OH)— 2-C₄H₃S (309) H CH₃ —CO—p-C₆H₄F (310) H CH₃ —CO— o-C₆H₄F (311) H CH₃ —CO— m-C₆H₄F (312) H CH₃—CO— p-C₆H₄Cl (313) H CH₃ —CO— m-C₆H₄Cl (314) H CH₃ —CO— C₆H₅ (315) HCH₃ —CO— 2-C₄H₃S (316) H CH₃ —CH(OH)— p-C₆H₄F (317) H CH₃ —CH(OH)—o-C₆H₄F (318) H CH₃ —CH(OH)— m-C₆H₄F (319) H CH₃ —CH(OH)— p-C₆H₄Cl (320)H CH₃ —CH(OH)— m-C₆H₄Cl (321) H CH₃ —CH(OH)— C₆H₅ (322) H CH₃ —CH(OH)—2-C₄H₃S (323) H CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F (324) H CH₃—C(p-C₆H₄F)(OH)— o-C₆H₄F (325) H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄F (326) HCH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (327) H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄Cl(328) H CH₃ —C(p-C₆H₄F)(OH)— C₆H₅ (329) H CH₃ —C(p-C₆H₄F)(OH)— 2-C₄H₃S(330) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (331) H CH₃ —C(C₆H₅)(OH)— o-C₆H₄F(332) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄F (333) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄Cl(334) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄Cl (335) H CH₃ —C(C₆H₅)(OH)— C₆H₅ (336)H CH₃ —C(C₆H₅)(OH)— 2-C₄H₃S (337) CH₃ H —CO— p-C₆H₄F (338) CH₃ H—C(C₆H₅)(OH)— p-C₆H₄F (339) CH₃ H —C(p-C₆H₄F)(OH)— p-C₆H₄F (340) CH₃ H—CH(OH)— p-C₆H₄F (341) H F —CO— p-C₆H₄F (342) H F —C(C₆H₅)(OH)— p-C₆H₄F(343) H F —C(p-C₆H₄F)(OH)— p-C₆H₄F (344) H Cl —CH(OH)— p-C₆H₄F (345) FCH₃ —CO— p-C₆H₄F (346) F CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (347) F CH₃—C(p-C₆H₄F)(OH)— p-C₆H₄F (348) Cl CH₃ —CH(OH)— p-C₆H₄F

EXAMPLES 349-416

[0085]

R¹ R² B Ar (349) H H —CO— p-C₆H₄F (350) H H —CO— o-C₆H₄F (351) H H —CO—m-C₆H₄F (352) H H —CO— p-C₆H₄Cl (353) H H —CO— m-C₆H₄Cl (354) H H —CO—C₆H₅ (355) H H —CO— 2-C₄H₃S (356) H H —CH(OH)— p-C₆H₄F (357) H H—CH(OH)— o-C₆H₄F (358) H H —CH(OH)— m-C₆H₄F (359) H H —CH(OH)— p-C₆H₄Cl(360) H H —CH(OH)— m-C₆H₄Cl (361) H H —CH(OH)— C₆H₅ (362) H H —CH(OH)—2-C₄H₃S (363) H H —C(p-C₆H₄F)(OH)— p-C₆H₄F (364) H H —C(p-C₆H₄F)(OH)—o-C₆H₄F (365) H H —C(p-C₆H₄F)(OH)— m-C₆H₄F (366) H H —C(p-C₆H₄F)(OH)—p-C₆H₄Cl (367) H H —C(p-C₆H₄F)(OH)— m-C₆H₄Cl (368) H H —C(p-C₆H₄F)(OH)—C₆H₅ (369) H H —C(p-C₆H₄F)(OH)— 2-C₄H₃S (370) H H —C(C₆H₅)(OH)— p-C₆H₄F(371) H H —C(C₆H₅)(OH)— o-C₆H₄F (372) H H —C(C₆H₅)(OH)— m-C₆H₄F (373) HH —C(C₆H₅)(OH)— p-C₆H₄Cl (374) H H —C(C₆H₅)(OH)— m-C₆H₄Cl (375) H H—C(C₆H₅)(OH)— C₆H₅ (376) H H —C(C₆H₅)(OH)— 2-C₄H₃S (377) H CH₃ —CO—p-C₆H₄F (378) H CH₃ —CO— o-C₆H₄F (379) H CH₃ —CO— m-C₆H₄F (380) H CH₃—CO— p-C₆H₄Cl (381) H CH₃ —CO— m-C₆H₄Cl (382) H CH₃ —CO— C₆H₅ (383) HCH₃ —CO— 2-C₄H₃S (384) H CH₃ —CH(OH)— p-C₆H₄F (385) H CH₃ —CH(OH)—o-C₆H₄F (386) H CH₃ —CH(OH)— m-C₆H₄F (387) H CH₃ —CH(OH)— p-C₆H₄Cl (388)H CH₃ —CH(OH)— m-C₆H₄Cl (389) H CH₃ —CH(OH)— C₆H₅ (390) H CH₃ —CH(OH)—2-C₄H₃S (391) H CH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄F (392) H CH₃—C(p-C₆H₄F)(OH)— o-C₆H₄F (393) H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄F (394) HCH₃ —C(p-C₆H₄F)(OH)— p-C₆H₄Cl (395) H CH₃ —C(p-C₆H₄F)(OH)— m-C₆H₄Cl(396) H CH₃ —C(p-C₆H₄F)(OH)— C₆H₅ (397) H CH₃ —C(p-C₆H₄F)(OH)— 2-C₄H₃S(398) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (399) H CH₃ —C(C₆H₅)(OH)— o-C₆H₄F(400) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄F (401) H CH₃ —C(C₆H₅)(OH)— p-C₆H₄Cl(402) H CH₃ —C(C₆H₅)(OH)— m-C₆H₄Cl (403) H CH₃ —C(C₆H₅)(OH)— C₆H₅ (404)H CH₃ —C(C₆H₅)(OH)— 2-C₄H₃S (405) CH₃ H —CO— p-C₆H₄F (406) CH₃ H—C(C₆H₅)(OH)— p-C₆H₄F (407) CH₃ H —C(C₆H₅F)(OH)— p-C₆H₄F (408) CH₃ H—CH(OH)— p-C₆H₄F (409) H F —CO— p-C₆H₄F (410) H F —C(C₆H₅)(OH)— p-C₆H₄F(411) H F —C(p-C₆H₄F)(OH)— p-C₆H₄F (412) H Cl —CH(OH)— p-C₆H₄F (413) FCH₃ —CO— p-C₆H₄F (414) F CH₃ —C(C₆H₅)(OH)— p-C₆H₄F (415) F CH₃—C(p-C₆H₄F)(OH)— p-C₆H₄F (416) Cl CH₃ —CH(OH)— p-C₆H₄F

EXAMPLE A Ampoules for Injection

[0086] A solution of 100 g of a compound of the general formula I and 5g of disodium hydrogenphosphate is adjusted to pH 6.5 using 2 Nhydrochloric acid in 3 l of double-distilled water, sterile filtered andfilled into injection ampoules, and lyophilized. Sterile conditions wereadhered to here. Each injection ampoule contains 5 mg of the activecomponent of the, general formula I.

EXAMPLE B

[0087] A mixture of 20 g of a compound of the general formula I is mixedwith 100 g of soya lecithin and 1400 g of cocoa butter with warming andpoured into hollows. Each suppository contains 20 mg of the activecomponent.

EXAMPLE C

[0088] A solution comprising 1 g of a compound of the general formula I,9.38 g of NaH₂PO₄×2 H₂O, 28.48 g of Na₂HPO₄×12 H₂O and 0.1 g ofbenzalkonium chloride is prepared using 940 ml of double-distilledwater. The solution is adjusted to pH 6.8 and made up to one litre withdouble-distilled water and sterilized by irradiation. This solution canbe used in the form of eye drops.

EXAMPLE D Ointment

[0089] 500 mg of a compound of the general formula I are blended with99.5 g of raw petroleum jelly under aseptic conditions.

EXAMPLE E Tablets

[0090] 100 g of a compound of the general formula I, 1 kg of lactose,600 g of microcrystalline cellulose, 600 g of cornstarch, 100 g ofpolyvinyl-pyrrolidone, 80 g of talc and 10 g of magnesium stearate aremixed and pressed in a customary manner to give tablets such that onetablet contains 100 mg of the active component.

EXAMPLE F Coated Tablets

[0091] Tablets are prepared as in Example 7 and then coated in a knownmanner with sucrose, maize starch, talc, tragacanth gum and colorants.

EXAMPLE G Capsules

[0092] Hard gelatin capsules are filled with a compound of the generalformula I in a known manner such that each capsule contains 5 mg of theactive component.

EXAMPLE H Inhalation Spray

[0093] 14 g of a compound of the general formula I are dissolved in 10 lof isotonic saline solution. The solution is filled into commerciallyobtainable spray containers which have a pump mechanism. The solutioncan be sprayed into the mouth or into the nose. One puff of spray(approximately 0.1 ml) corresponds to a dose of 0.14 mg of a compound ofthe general formula I.

1. Arylpiperazine compounds of the formula I

where A is a fused heteroaromatic or heteroaliphatic ring comprising oneor two nitrogen atoms, B is —CO— or —CHOH— or —C(Ar)(OH)— R¹ and R²independently of one another are H, alkyl, C₁-C₆ or halogen Ar is phenylor thiophene, which is unsubstituted or monosubstituted orpolysubstituted by halogen, NO₂ or CN and n is 1, 2, 3 or 4, and theirsalts and solvates.
 2. Compounds of the formula I according to one ofthe preceding claims, characterized in that the group

has one of the following meaning:


3. Compounds selected from the following group of compounds 1a to 1h:

and their salts and solvates.
 4. Compounds of the formula I according toclaim 1 and their physiologically acceptable salts or solvates aspharmaceutical active compounds.
 5. Compounds of the formula I accordingto claim 1 and their physiologically acceptable salts or solvates as D₂receptor antagonists and/or 5HT_(1A) antagonists.
 6. Compounds of theformula I according to claim 1 and their physiologically acceptablesalts or solvates for use in the control of diseases.
 7. Pharmaceuticalpreparation characterized in that it contains at least one compound ofthe formula I according to claim 1 and/or one of its physiologicallyacceptable salts or solvates.
 8. Use of compounds of the formula Iaccording to claim 1 and/or their physiologically acceptable salts orsolvates for the production of a medicament.
 9. Use of compounds of theformula I according to claim 1 and/or their physiologically acceptablesalts or solvates for the production of a medicament for the treatmentof illnesses of the central nervous system, in particular of mentaldisorders of the schizophrenia type and for the control of psychoticanxiety states.
 10. Process for the preparation of compounds of theformula I and their salts and solvates, characterized in that a compoundof the formula II

in which R¹, R² and A have the meaning indicated above, is reacted witha compound of the formula III

 in which Ar, B and n have the meaning indicated above and L is aleaving group and, if B has the meaning —CO—, the group B is optionallyhydrogenated, alkylated or arylated and, if appropriate, a basic oracidic compound of the formula I is converted into one of its salts orsolvates by treating with an acid or base.